The incidence and geographic distribution of Lyme disease in the U.S. has increased steadily since its first description in 1977. Efforts to stem the spread of the disease through controlling the population of its tick vector and/or the mouse reservoirs of the disease have met with only limited success. The only approved human vaccine to protect against Lyme disease was recently removed from the market by its manufacturer further highlighting the need for new approaches to controlling the disease. In this project, we propose the development of an orally- available vaccine targeted towards the mouse and tick reservoirs of the disease. The project is modeled on the highly successful oral rabies vaccine, Raboral, which uses a vaccinia virus (VV) vector to deliver its immunogen to wild foxes and raccoons. We will take advantage of the enormous amount of immunogenicity and safety data that has been generated for vaccinia virus in hopes of rapidly developing a release-able vaccine. The vaccine itself will consist of outer surface protein A (OspA) recombinantly expressed from a VV vector. OspA was the antigen used in the human vaccine. Extensive research has shown that it is immunogenic in mice, that mice vaccinated against OspA are protected against infection with Borrelia burgdorferi and that B. burgdorferi infected ticks feeding on mice vaccinated with OspA are sterilized of their infection and cannot transmit the disease to other animals. Prior attempts to use OspA to vaccinate wild animals have been hampered by the lack of an efficient, oral delivery system which is both stable under natural environmental conditions and can generate an intense immune response. The three aims of this project are to: 1) create a recombinant VV expressing OspA (W/OspA); 2) establish the kinetics and durability of the immune response to the recombinant W/OspA; and 3) test the efficacy of W/OspA administered orally in preventing transmission of B. burgdorferi to mice and in sterilizing infection in infected ticks.